During the most current funding period, we have continued to recruit a cohort of non-HIV cryptococcal diseased individuals. We have thus far recruited 80 patients and have begun immunological and genetic characterizations in collaboration with Dr. B. Bielekova from NINDS. A subset of these patients that were not responding to conventional therapy was found to exhibit an overly robust immune response with ventriculitis and cerebral edema which was found to be steroid responsive. Immunophenotyping has identified increased T cell and B cell activation in the cerebrospinal fluid of these patients which is steroid repressible. Since prolonged steroid therapy can be detrimental, we are also testing the response of steroid sparing agents in controlling these severe infections. In collaboration with Sarah Browne LCID/NIAID/NIH, we have identified 4 patients with C. gattii infection who have high levels of neutralizing anti-GMCSF antibody. In addition, we have set up a collaboration with Dr. Kieren Marr at Johns Hopkins and have obtained UO1 funding to fund a database and sample collection from 32 sites across the US. This will allow testing of genetic and immunological hypotheses generated from the cohort at the NIH clinical center. Furthermore, in collaboration with the University of Illinois, a cohort of candidemia patients has been used to identify a key genetic locus associated with poor outcome and have obtained a mouse knockout strain and are conducting backcrossing experiments to more rigorously test and validate the genetic associations found in the clinical outcomes trial.